Abstract
The entry of enveloped viruses into their host cells involves several successive steps, each one being amenable to therapeutic intervention. Entry inhibitors act by targeting viral and/or cellular components, through either the inhibition of protein-protein interactions within the viral envelope proteins or between viral proteins and host cell receptors, or through the inhibition of protein-lipid interactions. Interestingly, inhibitors that concentrate into/onto the membrane in order to target a protein involved in the entry process, such as arbidol or peptide inhibitors of the human immunodeficiency virus (HIV), could allow the use of doses compatible with therapeutic requirements. The efficacy of these drugs validates entry as a point of intervention in viral life cycles. Strategies based upon small molecule antiviral agents, peptides, proteins or nucleic acids, would most likely prove efficient in multidrug combinations, in order to inhibit several steps of virus life cycle and prevent disease progression.
Highlights
Therapeutic inhibition of virus infection could involve several strategies and target various steps of virus life cycle such as cell entry, virus replication or the assembly and release of newly-formed virions
The penetration of an enveloped virus into its target cell is the first step of the viral replication cycle, and each stage could constitute a potential target for an inhibitor (Figure 1) [1]
In spite of resistance issues, the successful development and regulatory approval of enfuvirtide, maraviroc or amantadine have shown that viral entry is a valid target for therapeutic intervention
Summary
Therapeutic inhibition of virus infection could involve several strategies and target various steps of virus life cycle such as cell entry, virus replication or the assembly and release of newly-formed virions. PH-dependent cell entry of an enveloped virus (orange): after attachment to receptor(s), the virus reaches the endosomal compartment where acidic pH induces conformational rearrangements in the viral envelope glycoprotein that mediates membrane fusion, leading to genome release at acidic pH. Membrane fusion of viruses displaying pH-dependent entry occurs within the acidic environment of endosomal compartments, where the pH induces the conformational changes of the fusion protein leading to the exposure of the fusion peptide. All these stages are potentially amenable to therapeutic intervention. The knowledge and understanding of antiviral strategies studied or applied for enveloped viruses could lead to the development of new inhibitors
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